Vaccines are administered to improve the development of antibodies with the help of adjuvants. Adjuvants are to retard the absorption of parenterally administered antigens and contribute to a long antigen stimulus. Thus, adjuvants act as enhancers of the immunogenic effect of antigens.
A well known adjuvant is the Freund adjuvant. In its intermediate form, it is a mineral oil-in-water emulsion which can provoke a substantial response from the immune system, while the finished form is produced by the addition of inactivated mycobacteria to the intermediate for considerably higher immunostimulation. The adjuvant action of inactivated mycobacteria is attributed to a growth fraction contained therein. The finished Freund adjuvant frequently causes granuloma formation at the site of the application. The original, finished Freund adjuvant is therefore used only for experimental purposes involving animals.
Aluminum compounds, in the form of hydroxides or phosphates, are frequently used in medicine as adjuvants. Through coupling with vaccine antigens, the so-called adsorbate, these aluminum compounds result in vaccines, the immunopotentiation action of which is explained by the resulting vaccine depots, from which the release of antigen for adsorption is retarded. The aggregation and settling tendencies of solid aluminum compounds, as well as the behavior of their residue, is a disadvantage of the use of these compounds.
A stable water-in-oil emulsion is a further development of an intermediate Freund adjuvant, which, as is well known, includes a mineral oil, a simple emulsifier such as mannitol monooleate, physiological salt solution and Tween 80. These components usually are dispersed with a strong homogenizer, and finished with specific vaccine antigens into the vaccine.
It is a common feature of all of these vaccines, which are based on the oil-in-water emulsion, that the antigen is dispersed only in the aqueous phase of the emulsion. Consequently, a correspondingly long depot action of the antigen is not achieved. Since the viscosity of water-in-oil emulsions is relatively high, it is difficult to administer them. Therefore, hypodermic needles with a large diameter must be used. Moreover, all generally used equipment requires intensive cleaning because of the oiling.
Granuloma may be formed at the site of the injection, as a result of which the antigens are rapidly incorporated over the lymph tracts.
According to the literature, the stability at 37.degree. C. does not exceed one week. After that, there is phase separation and the emulsion is destroyed.
It is also a disadvantage that high-power homogenizers are absolutely essential for producing these water-in-oil emulsions. It is furthermore, disadvantageous that the emulsion must be transported and kept refrigerated.
In the East German patent No. 265 992, an adjuvant is described for immunization as well as methods for producing the same. The oil-in-water emulsion that is used, results in a vaccine having a low viscosity, and requires no special technique of administration. The apparatus can be cleaned without extra expense and the use of the suggested dipolar aprotic solvent guarantees the dispersal of the antigen in the aqueous and oil phases thus, increasing the immunizing effect. Relatively little mechanical energy is required for producing the oil-in-water emulsion, so that simple stirring is sufficient for producing an emulsion of this type. The oil portion of the emulsion is a mineral oil and can optionally contain silicone oils.
It is a disadvantage of this adjuvant that the use of mineral oils, in this case paraffin oils, is associated with a series of problems with regard to the stability of the oil-in-water emulsion. For example, the viscosity of the mineral oil can be varied only within narrow limits. This causes relatively large particles to be formed during the dispersal of the oil droplets. Larger oil droplets cause an increase in the overall viscosity of the emulsion and the associated disadvantages and also unfavorably affect the stability of the emulsion, because cream formation in the oil cannot be avoided, particularly after the emulsion has been standing for some time. The polydisperse particle size distribution of the oil droplets in this oil-in-water emulsion also leads to unstable relationships and histo-incompatibilities.
A further disadvantage is the residue behavior of the mineral oils, which results in incompatibilities with the organism and, when used in animals, can render the animals unfit for human consumption.
Mineral oils also tend to attack certain antigens and thus make the vaccines ineffective.
The use of dipolar aprotic solvents, such as dimethyl sulfoxide, in conjunction with mineral oils will also not bring about the expected depot effect. Evidently, a slow resupplying of antigens from the oil phase into the aqueous phase (boosting), by the exchange of the antigens between the aqueous phase and the oil phase is not optimally obtained in the presence of a dipolar aprotic solvent.